WO2014105777A1 - Sel de dichlohydrate de cobicistat - Google Patents

Sel de dichlohydrate de cobicistat Download PDF

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Publication number
WO2014105777A1
WO2014105777A1 PCT/US2013/077394 US2013077394W WO2014105777A1 WO 2014105777 A1 WO2014105777 A1 WO 2014105777A1 US 2013077394 W US2013077394 W US 2013077394W WO 2014105777 A1 WO2014105777 A1 WO 2014105777A1
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WO
WIPO (PCT)
Prior art keywords
cobicistat
dihydrochloride salt
solid state
salts
salt according
Prior art date
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PCT/US2013/077394
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English (en)
Other versions
WO2014105777A8 (fr
Inventor
Jacob Rendell
Ariel MITTELAMAN
Sofia Gorohovsky
Motti Erlich
Original Assignee
Assia Chemical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication date
Application filed by Assia Chemical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Assia Chemical Industries Ltd.
Priority to EP13819171.3A priority Critical patent/EP2938603A1/fr
Priority to US14/654,202 priority patent/US20160200716A1/en
Priority to JP2015550713A priority patent/JP2016504364A/ja
Publication of WO2014105777A1 publication Critical patent/WO2014105777A1/fr
Publication of WO2014105777A8 publication Critical patent/WO2014105777A8/fr
Priority to IL239281A priority patent/IL239281A0/en
Priority to HK16103508.1A priority patent/HK1215571A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention encompasses Cobicistat salts, solid state forms thereof and pharmaceutical compositions thereof.
  • Cobicistat is under investigation as a CYP3A4 inhibitor. It also has been investigated as an HIV drug-boosting agent for use in antiretroviral combination therapy as an alternative to Ritonavir. Cobicistat is also a component of Stribild (including
  • WO 2012/151 165 discuss the difficulties associated with handling and processing Cobicistat due to its solid state properties.
  • Cobicistat has a non free-flowing nature that make it particularly difficult to process and to formulate (e.g. as a tablet).
  • Polymorphism the occurrence of different crystalline forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state ( 13 C-) NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, improving hygroscopicity or stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
  • Discovering new salts, solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New salts and solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Cobicistat. Summary of the Invention
  • the present invention provides Cobicistat dihydrochloride, methanesulfonate, acetate, hydrobromide, salicylate, nitrate, and dinitrate salts.
  • the present invention also provides solid state forms of the salts, and pharmaceutical compositions comprising the salts or solid state forms thereof.
  • compositions may comprise only Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate, or Cobicistat dinitrate as the active pharmaceutical ingredient (API), or comprise a combination of one or more of the Cobicistat salts of the present invention with one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir.
  • API active pharmaceutical ingredient
  • the present invention also encompasses the use of one or more of the Cobicistat salts of the present invention and solid state forms thereof of the present invention for the preparation of: 1) Cobicistat free base and solid state forms thereof and/or pharmaceutical compositions thereof, 2) other Cobicistat salts and solid state forms thereof and/or pharmaceutical compositions thereof and 3) Cobicistat free base or other Cobicistat salts and solid state forms thereof in a combination with one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir and/or pharmaceutical compositions thereof.
  • the present invention further comprises pharmaceutical formulations as well as a process for preparing said pharmaceutical formulations.
  • the process comprises combining one or more of the Cobicistat salts of the present invention, and solid state forms thereof, optionally with one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir, with at least one pharmaceutically acceptable excipient.
  • the salts, solid state forms thereof and the pharmaceutical compositions and formulations of the present invention can be used as medicaments, particularly wherein the Cobicistat salt or its solid state forms acts as a pharmacokinetics enhancer for a co- administered drug for the treatment of HIV infections.
  • the present invention also provides a method of treating HIV infections, comprising administering a therapeutically effective amount of one or more of the Cobicistat salts of the present invention, or solid state forms thereof, or at least one of the above pharmaceutical compositions or formulations, in combinations with an effective amount of one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir to a subject suffering from HIV infections, or otherwise in need of the treatment.
  • a method of treating HIV infections comprising administering a therapeutically effective amount of one or more of the Cobicistat salts of the present invention, or solid state forms thereof, or at least one of the above pharmaceutical compositions or formulations, in combinations with an effective amount of one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir to a subject suffering from HIV infections, or otherwise in need of the treatment.
  • Figure 1 shows an X-ray powder diffractogram of amorphous Cobicistat
  • Figure 2 shows an X-ray powder diffractogram of amorphous Cobicistat acetate salt.
  • Figure 3 shows an X-ray powder diffractogram of amorphous Cobicistat
  • Figure 4 shows an X-ray powder diffractogram of amorphous Cobicistat
  • Figure 5 shows an X-ray powder diffractogram of amorphous Cobicistat salicylate.
  • Figure 6 shows an X-ray powder diffractogram of amorphous Cobicistat nitrate salt.
  • Figure 7 shows an X-ray powder diffractogram of amorphous Cobicistat dinitrate salt.
  • Figure 8 shows a solid-state 13 C NMR spectrum of amorphous Cobicistat dihydrochloride salt in the 0-200 ppm range.
  • Figure 9 shows a microscope image of Cobicistat dihydrochloride salt prepared according to example 5.
  • Figure 10 shows a microscope image of Cobicistat monohydrochloride salt prepared according to example 7.
  • Figure 11 shows an X-ray powder diffractogram of a crystalline calcium salt of (bis[(S)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanoate] ("CBC8"-Ca).
  • Figure 12 shows two glass cylinders filled with about 0.30g of Cobicistat
  • Figure 13 shows an XRPD pattern of a crystalline methyl (S)-2-(3-((2- isopropylthiazol-4-yl)methyl)-3 -methylureido)-4-morpholinobutanoate oxalate ("CBC8-Me oxalate").
  • the present invention encompasses Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate and Cobicistat dinitrate salts and solid state forms thereof.
  • Solid state properties of Cobicistat salts can be influenced by controlling the conditions under which the salts, e.g., Cobicistat dihydrochloride methanesulfoniate, acetate, , hydrobromide, salicylate, nitrate and dinitrate salts, are obtained in solid form.
  • Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat dihydrochloride, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate and Cobicistat dinitrate salts and solid state forms thereof of the invention are substantially free of Cobicistat free base and/or any other salts, polymorphic forms, or of specified polymorphic forms of Cobicistat, respectively.
  • the salts and solid state forms of the present invention contain 20% (w/w) or less of Cobicistat free base and/or any other salts, polymorphs, or of a specified polymorph of Cobicistat.
  • the salts and solid state forms of the present invention contain 10% (w/w) or less, 5% (w/w) or less, 2% (w/w) or less, 1% (w/w) or less, 0.5% (w/w) or less, or 0.2% (w/w) or less of Cobicistat free base and/or any other salts, polymorphs, or of a specified polymorph of
  • the salts and solid state forms of Cobicistat of the present invention contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of Cobicistat free base and/or any other salts, solid state forms or of a specified polymorph of Cobicistat.
  • WO 2009/135179 and WO 2012/151 165 discuss the difficulties associated with handling and processing Cobicistat due to its solid state properties. Improving the physical properties of Cobicistat may be accomplished by combining it with a solid carrier as described in WO 2009/135179.
  • the inert carrier contributes to the overall volume and weight of the solid material, so in formulation more material is needed, which is undesirable, particularly since antiretroviral drugs are often administered in combination.
  • Cobicistat Another possibility for improving the physical properties of Cobicistat is by formation of alternative solid forms.
  • the known salts and solid state forms of Cobicistat e.g. the monohydrochloride salt as disclosed in WO 2012/151165
  • Cobicistat monohydrochloride prepared according to the prior art WO 2012/151 165
  • the monohydrochloride salt has a low bulk density.
  • Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat dihydrochloride, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate and Cobicistat dinitrate salts of the present invention have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability- such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.
  • a solid state form such as a crystal form or amorphous form, may be referred to herein as being characterized by graphical data "as depicted in” or “as substantially depicted in” a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called
  • the term "isolated" in reference to Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate, and Cobicistat dinitrate salts or solid state forms thereof of the present invention corresponds to Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate, and Cobicistat dinitrate salts or solid state form thereof that is physically separated from the reaction mixture in which it is formed.
  • the terms "powder” or “powder form” in reference to Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate, and Cobicistat dinitrate salts or solid state forms thereof of the present invention corresponds to Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate, and Cobicistat dinitrate salts or solid state form thereof relates to a solid that is a free-flowing, handleable, particulate form of said Cobicistat salts.
  • the terms "powder” or “powder form” in reference to Cobicistat salts or solid state form thereof relates to a solid compound in the forms of particles or granules, wherein the particles or granules can be poured.
  • the powders are dry particles.
  • the XRPD measurements are taken using copper Kcc radiation wavelength 1.5418 A.
  • a thing e.g., a reaction mixture
  • room temperature or “ambient temperature”, often abbreviated as "RT.”
  • RT room temperature
  • room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • the amount of solvent employed in a chemical process may be referred to herein as a number of "volumes” or “vol” or “V.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
  • v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.
  • a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, typically about 16 hours.
  • reduced pressure refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.
  • the Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate or Cobicistat dinitrate salt is isolated.
  • the Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate and Cobicistat dinitrate salts are solid, preferably, in a powder form.
  • the present invention comprises Cobicistat dihydrochloride salt.
  • the Cobicistat dihydrochloride salt may be in amorphous form.
  • the amorphous form of Cobicistat dihydrochloride acid salt can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern (XRPD) substantially as depicted in Figure 3; a solid-state 13 C NMR spectrum with broad signals at 31.4, 64.0 and 183.4 ⁇ 0.3 ppm; a solid-state 13 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 120 to 200 ppm of 10.4, 27.5 and 54.4 ⁇ 0.2 ppm; a 13 C NMR spectrum as depicted in Figure 8; and combinations of these data.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 120 to 200 ppm is typically at 129.0 ⁇ 1 ppm.
  • the amorphous form of Cobicistat dihydrochloride acid salt may be characterized by each of the above characteristics alone and/or by all possible combinations, e.g. by a solid- state 13 C NMR spectrum with broad signals at 31.4, 64.0 and 183.4 ⁇ 0.3 ppm and an X-ray powder diffraction pattern as depicted in Figure 3.
  • the Cobicistat dihydrochloride salt is in a powder form.
  • Cobicistat dihydrochloride has advantageous properties.
  • Cobicistat monohydrochloride salt generally solidifies from an oil to afford material having unfavorable morphology (as shown in Figure 10), while Cobicistat dihydrochloride of the present invention is a highly flowable powder material having a particle-shaped morphology as is demonstrated in Figure 9.
  • Cobicistat dihydrochloride is substantially higher than that of the monohydrochloride salt (as is demonstrated in Figure 12).
  • a material having higher bulk density typically exhibits better filterability and flowability.
  • a good flowability of a powder is particularly important in the high- volume formulation of the API into solid dosage forms, which necessitates rapid, uniform and consistent filling of cavities such as capsules, or tablet presses. Poor flow characteristics cause slow and nonuniform press feeding and difficulties in ensuring a consistent, reproducible fill of the cavities.
  • the Cobicistat dihydrochloride of the present invention has favorable technological (physical and mechanical) properties, which offers advantages during handling and processing, e.g., in tablet formulation processes.
  • the present invention comprises a Cobicistat
  • the Cobicistat methanesulfonate salt may be in amorphous form.
  • the amorphous form of the Cobicistat methanesulfonate salt can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1.
  • the present invention comprises a Cobicistat acetate salt.
  • the Cobicistat acetate salt may be in amorphous form.
  • the amorphous form of the Cobicistat acetate salt can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2.
  • the present invention comprises a Cobicistat hydrobromide salt.
  • the Cobicistat hydrobromide salt may be in amorphous form.
  • the amorphous form of the Cobicistat hydrobromide salt can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4.
  • the present invention comprises a Cobicistat salicylate salt.
  • the Cobicistat salicylate salt may be in amorphous form.
  • the amorphous form of the Cobicistat salicylate salt can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 5.
  • the present invention comprises a Cobicistat nitrate salt.
  • the Cobicistat nitrate salt may be in amorphous form.
  • Cobicistat nitrate salt can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 6.
  • the present invention comprises a Cobicistat dinitrate salt.
  • the Cobicistat dinitrate salt may be in amorphous form.
  • the amorphous form of the Cobicistat dinitrate salt can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 7.
  • Cobicistat dihydrochloride, Cobicistat methanesulfonate, Cobicistat acetate, Cobicistat hydrobromide, Cobicistat salicylate, Cobicistat nitrate and Cobicistat dinitrate salts and solid state forms thereof can be used to prepare pharmaceutical compositions comprising one or more of the Cobicistat salts as the only API, or a
  • Cobicistat salts with one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir.
  • the present invention comprises pharmaceutical compositions comprising one or more of the Cobicistat salts of the present invention as the only API, or a combination of any one of the Cobicistat salts mentioned above with one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir.
  • the pharmaceutical composition is a solid
  • composition and the Cobicistat salts retain their solid state forms.
  • compositions can be prepared by a process comprising combining one or more of the Cobicistat salts of the present invention and solid state forms thereof, optionally with one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir,
  • the invention comprises pharmaceutical formulations comprising a pharmaceutical composition as described above, and at least one
  • the formulations are typically prepared by combining said pharmaceutical compositions with at least one excipient and bringing them into the desired dosage form such as tablets, or reconstitutable powders for injection.
  • Cobicistat salts and solid state forms thereof can also be used to prepare Cobicistat free base and/or other salts of Cobicistat, as well as solid state forms thereof and/or pharmaceutical compositions thereof.
  • These pharmaceutical compositions can optionally contain one or more additional APIs such as Elvitegravir, Emtricitabine, or Tenofovir.
  • the present invention also encompasses processes for preparing Cobicistat free base and/or another salt of Cobicistat.
  • Cobicistat free base can be prepared by a process comprising preparing any one of the Cobicistat salts of the present invention, or solid state forms thereof, by the processes of the present invention, and converting it to Cobicistat free base.
  • the conversion can be done, for example, by a process comprising basifying any one of the above described Cobicistat salt and/or solid state forms thereof, to obtain Cobicistat free base.
  • the Cobicistat free-base can then be converted to another salt, if required, by reacting it with a suitable acid.
  • another Cobicistat salt can be prepared by salt switching, i.e., reacting any one of the above described Cobicistat salt and/or solid state forms thereof, with an acid, having a pK a which is lower than the pK a of the acid of the first Cobicistat salt.
  • the Cobicistat salts of the present invention and/or solid state forms thereof of the present invention in combinations with one or more other APIs as described above can also be used as a medicament.
  • the present invention further encompasses 1) the use of the above-described
  • Cobicistat salts and solid state forms thereof optionally, in a combination with one or more other APIs, in the manufacture of a pharmaceutical composition, and 2) the use of the salts, solid state forms thereof and the pharmaceutical compositions of the present invention as medicaments, particularly as a wherein the Cobicistat salt or its solid state forms acts as a pharmacokinetics enhancer for a co-administered drug for the treatment of HIV infections.
  • composition comprising any one or a combination of the Cobicistat salts described herein, optionally, in a combination with an effective amount of one or more other APIs such as Elvitegravir, Emtricitabine, or Tenofovir.
  • the present invention further describes Calcium and Barium salts of (bis[(S)-2-(3-((2- isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanoate] ("CBC8”), an intermediate in the preparation of Cobicistat as well as processes for their preparation.
  • CBC8 Ca and Ba salts may be in a crystalline or in an amorphous form.
  • the present invention describes a crystalline form of CBC8 calcium salt.
  • the crystalline form of the CBC8 calcium salt is characterized by data selected from one or more of the following: X-ray powder diffraction pattern having peaks at 5.2, 10.1, 16.7, 18.5 and 21.1 degrees two theta ⁇ 0.2 degrees two theta; an X-ray powder diffraction pattern as depicted in Figure 1 1; and combinations of these data.
  • the crystalline form of CBC8-Ca salt may be further characterized by the X-ray powder diffraction pattern having peaks at 5.2, 10.1, 16.7, 18.5 and 21.1 degrees two theta ⁇ 0.2 degrees two theta and also having one, two, three, four or five additional peaks selected from: 14.6, 20.3, 21.8, 22.2 and 25.0 ⁇ 0.2 degrees two-theta.
  • the present invention describes a crystalline form of CBC8- Me oxalate.
  • the crystalline form of CBC8-Me oxalate is characterized by data selected from one or more of the following: X-ray powder diffraction pattern having peaks at: 6.5, 16.9, 22.5, 24.0 and 25.9 degrees two theta ⁇ 0.2 degrees two theta; an X-ray powder diffraction pattern as depicted in Figure 13; and combinations of these data.
  • the crystalline form of CBC8-Me oxalate may be further characterized by by the X-ray powder diffraction pattern having peaks at 6.5, 16.9, 22.5, 24.0 and 25.9 degrees two theta ⁇ 0.2 degrees two theta and also having one, two, three, four or five additional peaks selected from: 11.3, 18.0, 20.3, 23.3 and 28.3 degrees two theta ⁇ 0.2 degrees two theta.
  • the present invention also encompasses processes for preparing Cobicistat free base using CBC8 calcium or barium salts or CBC8-Me oxalate.
  • Cobicistat free base can be prepared by a process comprising preparing CBC8 Calcium or Barium salts and solid state forms, by the processes of the present invention, and converting it to Cobicistat free base.
  • the samples were analyzed on ARL (SCINTAG) powder X-Ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 A was used. Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05°, and a rate of 3 deg/min.
  • Microscope imaging Microscope pictures were taken using Leica light microscope DM2500 P equipped with Digital camera DFC290. Samples for microscope pictures were prepared by suspending in mineral oil.
  • the starting material Cobicistat can be prepared according to the following process: A 250 mL reactor equipped with a mechanical stirrer and a condenser was charged with 2-[3-(2-isopropyl-thiazol-4-ylmethyl)-3-methyl-ureido]-4-morpholin-4-yl-butyric acid (11.4 g), dichloromethane (“DCM”) (100 mL), and ⁇ , ⁇ -Diisopropylethylamine (“DIPEA”) (5.5 mL). The resulting mixture was cooled to 0°C, after which 1 -hydroxybenzotriazol hydrate (“HOBt.H 2 0”) (4.24 g) was added.
  • DCM dichloromethane
  • DIPEA ⁇ , ⁇ -Diisopropylethylamine
  • the starting material Cobicistat can be prepared according to the following process:
  • Example 2 Preparation of Cobicistat dihydrochloride A 50 mL round-bottomed flask was charged with Cobicistat (0.5 g, 1 eq) and MTBE
  • Cobicistat (0.5 g) and Me-THF (20V) were combined to obtain a reaction mixture.
  • the reaction mixture was stirred at 70°C for 0.5 h to obtain a clear solution.
  • 4M HCl/dioxane solution (0.5 mL, 3.1 eq) was added drop-wise, resulting in precipitation of a white solid.
  • the mixture was cooled to ambient temperature by removing the heating source, stirred for 3 h, filtered and washed with Me-THF.
  • the filter cake was dried for 16h in a vacuum oven at 50°C to give Cobicistat dihydrochloride salt as an amorphous white solid having morphology similar to that shown in Figure 9 (0.48 g,).
  • Cobicistat (4.0 g) and MTBE (20V) were mixed and heated to reflux. Stirring was continued at the same temperature for 0.5h to obtain a clear solution. Then, 4M HCl/dioxane solution (2.7 mL, 2.1 eq) was added drop-wise, resulting in precipitation of a white solid. The mixture was cooled to room temperature by removal of the heating source, and then stirred for 3 h. The white solid was filtered and washed with MTBE. The filter cake was dried over night in a vacuum oven at 40°C to give Cobicistat dihydrochloride salt as a white powder having morphology similar to that shown in Figure 9 (4.40 g, >99%, purity - 98.4%,).
  • Cobicistat (4.0 g) and MTBE (20V) were mixed and heated to reflux. Stirring was continued at the same temperature for 0.5h to obtain a solution.
  • the resulting solution was cooled to 50°C and a 4M HCl/dioxane solution (4.0 mL, 3.1 eq) was added drop-wise, resulting in the precipitation of a solid.
  • the mixture was cooled to ambient temperature by removal of the heating source, and then stirred for 3 h, filtered and washed with MTBE.
  • the isolated solid was dried over night in a vacuum oven at 40°C to give Cobicistat dihydrochloride salt as a white powder having the morphology shown in Figure 9 (4.38 g, >99%, purity - 97.5%).
  • Example 7 (Reference): Preparation of Cobicistat monohydrochloride salt (according to WO 2012/151165, example 7)
  • Cobicistat (5.0 g) was mixed with HCl/EtOH 3.38% solution (5.6 g) at ambient temperature. Stirring of the resulting mixture was continued for 15 min affording a clear solution. Then, MTBE (68 mL) was added drop-wise resulting in the precipitation of an oily mass. The mixture was concentrated under vacuum to about 10 ml. To the resulting mixture, MTBE (65 mL) was added drop-wise resulting in the precipitation of an oily mass. Stirring was continued at RT for 3 h and the solvent was removed by decantation. The resulting product mass was dried over night in a vacuum oven at 40°C to afford Cobicistat monohydrochloride salt as an amorphous solid having the morphology shown in Figure 10 (5.0 g, purity - 98.6%)
  • Example 10 Preparation of Cobicistat methanesulfonate A 50 mL round-bottomed flask was charged with Cobicistat (0.5 g) and MTBE (10 mL, 20 V). The mixture was stirred at reflux temperature for 0.5 h. to obtain a yellow solution. Then, methanesulfonic acid (0.1 mL, 2.5 eq) was added in one portion. The mixture was cooled to ambient temperature, stirred at RT for 3 h, and then filtered. The filter cake was dried over night in a vacuum oven at 40°C to give Cobicistat methanesulfonate as an amorphous off- white solid (0.56 g).
  • a 50 mL round-bottomed flask was charged with Cobicistat (0.5 g, 1 eq) and MTBE (10 mL, 20V) to obtain a reaction mixture.
  • the reaction mixture was heated and stirred at reflux temperature for 0.5 h.
  • To the resulting yellow solution was added by one portion a solution of acetic acid (0.04 mL, 1.1 eq) in MTBE (1 mL, 2V) at the same temperature.
  • the mixture was cooled to ambient temperature by removal of the heat source, and stirring was continued at RT over night.
  • n-heptane (10 mL, 20V) was added by one portion, which led to the precipitation of an oily mass.
  • the resulting mixture was stirred at RT for 3 h.
  • Cobicistat monohydrochloride and dihydrochloride prepared according to examples 7 and 5 respectively, (about 0.30 g) were freely poured into two glass cylinders without compaction. While 0.30g of Cobicistat monohydrochloride filled a volume of almost 5ml, 0.30g of Cobicistat dihydrochloride filled a volume of less than 2ml. The obtained results are shown in figure 12.
  • Example 20 Preparation of crystalline calcium bis[(S)-2-(3-((2-isopropylthiazol-4- yl)methyl)-3-methylureido)-4-morpholinobutanoate]
  • Example 21 Preparation of amorphous calcium bis[(S)-2-(3-((2-isopropylthiazol-4- yl)methyl)-3-methylureido)-4-morpholinobutanoate]
  • CBC8-Me oxalate (20g) was dissolved in water (37ml), dichloromethane (“DCM”) (112ml) and 15% KHCO 3 (106.8g) were added. The phases were separated, and the organic phase was washed with water (74ml) and evaporated to dryness. The residue was dissolved in water (10ml) and Ca(OH) 2 (1.59g) was added and the solution was stirred for 1.5h at 25°C.
  • DCM dichloromethane
  • KHCO 3 106.8g
  • Example 22 Preparation of amorphous barium bis[(S)-2-(3-((2-isopropylthiazol-4- yl)methyl)-3-methylureido)-4-morpholinobutanoate]
  • CBC8-Me oxalate (lOg) was dissolved in water (18.5ml), DCM (56ml) and 15% KHC0 3 (53.4g) were added. The phases were separated, and the organic phase was washed with water (37ml) and evaporated to dryness. The residue was dissolved in water (20ml) and Ba(OH) 2 ' 8H 2 0 (3.54g) was added and the solution was stirred for lh at 25°C and dried by codistillation with diisopropylether at 50°C. Diisopropylether (50ml) was added and the mixture was stirred for 15h at 25°C.
  • Example 23 Preparation of a crystalline form of calcium bis[(S)-2-(3-((2- isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanoate] :
  • Example 24 Preparation of l,3-thiazol-5-ylmethyl [(2 ?,5 ?)-5- ⁇ [(2S)-2-[(methyl ⁇ [2- (propan-2-yl)-l,3-thiazol-4-yl]methyl ⁇ carbamoyl)amino]-4-(morpholin-4- yl)butanoyl]amino ⁇ -l,6-diphenylhexan-2-yl] carbamate (Cobicistat)
  • Example 25 Preparation of crystalline form of Compound methyl (S)-2-(3-((2- isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanoate oxalate
  • MIBK methy isobutyl lketone

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Abstract

La présente invention concerne du sel de dihydrochlorure de Cobicistat, et des compositions pharmaceutiques correspondantes.
PCT/US2013/077394 2012-12-26 2013-12-23 Sel de dichlohydrate de cobicistat WO2014105777A1 (fr)

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EP13819171.3A EP2938603A1 (fr) 2012-12-26 2013-12-23 Sel de dichlohydrate de cobicistat
US14/654,202 US20160200716A1 (en) 2012-12-26 2013-12-23 Cobicistat dichlohydrate salt
JP2015550713A JP2016504364A (ja) 2012-12-26 2013-12-23 コビシスタット塩
IL239281A IL239281A0 (en) 2012-12-26 2015-06-08 Dihydrochloride salt of cubicistat
HK16103508.1A HK1215571A1 (zh) 2012-12-26 2016-03-24 二鹽酸科比思特

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2015079415A1 (fr) * 2013-11-29 2015-06-04 Mylan Laboratories Ltd. Dispersion solide de cobicistat amorphe
CN105732538A (zh) * 2014-12-09 2016-07-06 杭州普晒医药科技有限公司 可比司他帕莫酸盐及其制备方法、药物组合物和用途
WO2016132378A3 (fr) * 2015-02-18 2016-10-27 Msn Laboratories Private Limited Nouveau procédé de préparation de carbamate de 1,3-thiazol-5-ylméthyl[(2r,5r)-5-{[(2s)-2-[(méthyl{[2-(propan-2-yl)- 1,3-thiazol-4-yl]méthyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphénylhexan-2-yle]
CN107513046A (zh) * 2016-06-15 2017-12-26 江苏福瑞生物医药有限公司 一种可比司他的合成方法

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US20100189687A1 (en) 2007-02-23 2010-07-29 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics
WO2012151165A1 (fr) 2011-05-02 2012-11-08 Gilead Sciences, Inc. Sels solides amorphes

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EP3696171A1 (fr) * 2006-07-07 2020-08-19 Gilead Sciences, Inc. Modulateurs de propriétés pharmacocinétiques d'agents thérapeutiques
EP2231628B1 (fr) * 2008-01-04 2015-10-28 Gilead Sciences, Inc. Inhibiteurs du cytrochrome p450
UA108738C2 (uk) * 2009-04-03 2015-06-10 Спосіб одержання інгібітора цитохром р450 монооксигенази та залучені проміжні сполуки

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US20100189687A1 (en) 2007-02-23 2010-07-29 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics
US8148374B2 (en) 2007-02-23 2012-04-03 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics
WO2009135179A2 (fr) 2008-05-02 2009-11-05 Gilead Sciences, Inc. Utilisation de particules supports solides pour améliorer l'aptitude au traitement d'un agent pharmaceutique
WO2012151165A1 (fr) 2011-05-02 2012-11-08 Gilead Sciences, Inc. Sels solides amorphes

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015079415A1 (fr) * 2013-11-29 2015-06-04 Mylan Laboratories Ltd. Dispersion solide de cobicistat amorphe
CN105732538A (zh) * 2014-12-09 2016-07-06 杭州普晒医药科技有限公司 可比司他帕莫酸盐及其制备方法、药物组合物和用途
WO2016132378A3 (fr) * 2015-02-18 2016-10-27 Msn Laboratories Private Limited Nouveau procédé de préparation de carbamate de 1,3-thiazol-5-ylméthyl[(2r,5r)-5-{[(2s)-2-[(méthyl{[2-(propan-2-yl)- 1,3-thiazol-4-yl]méthyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphénylhexan-2-yle]
US10351556B2 (en) 2015-02-18 2019-07-16 Msn Laboratories Private Limited Process for the preparation of 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2s)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4YL] methyl} carbamoyl) amino]-4-(morpholin-4-yl)butanoyl]amino)-1,6-diphenylhexan-2-yl]carbamate
CN107513046A (zh) * 2016-06-15 2017-12-26 江苏福瑞生物医药有限公司 一种可比司他的合成方法

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